Technical Field
The present invention relates to N-heterocyclic carbene gold(I) dithiocarbamate complexes with anticancer or antitumor properties, and pharmaceutical compositions and uses thereof.
Description of the Related Art
The “background” description provided herein is for the purpose of generally presenting the context of the disclosure. Work of the presently named inventors, to the extent it is described in this background section, as well as aspects of the description which may not otherwise qualify as prior art at the time of filing, are neither expressly or impliedly admitted as prior art against the present invention.
Organometallic compounds of coinage metals (Cu, Ag and Au) have extensively been investigated owing to their diverse applications in bioinorganic and medicinal chemistry. Among coinage metals, gold complexes have attracted considerable attention in the treatment of many chronic diseases, such as rheumatoid arthritis, bronchial asthma and cancer due to their physicochemical, biological and pharmacological properties. Both gold(I) and gold(III) complexes bearing different functional ligands have numerous bio-medical applications [K. Nomiya, R. S. Yamamoto, Noghuchi, H. Yokoyama, N. C. Kasuga, K. Ohyama, C. Kato, J. Inorg. Biochem. 95 (2003) 208-220; T. McCormick, W.-L. Jia, S. Wang, Inorg. Chem. 45 (2006) 147-155; S. S. Al-Jaroudi, M. I. M. Wazeer, A. A. Isab, S. Altuwaijri, Polyhedron (2013) 434-442; R. B. Bostancioglu, K. Isik, H. Genc, K. Benkli, A. T. Koparal, Med. Chem. 27 (2012) 458-466—each incorporated herein by reference in their entirety].
Gold(I) complexes are potential chrysotherapeutic agents, which manifest outstanding antiproliferative activity against specific human cancer cell lines that are resistant or sensitive to classical chemotherapeutic platinum drugs [S. H. van Rijt, P. J. Sadler, Drug Discov. Today 14 (2009) 1089-1097—incorporated herein by reference in its entirety]. The novelty of Au(I) based drugs is the characteristic molecular structure that allows them to overcome resistance pathways, which were encountered in platinum-based chemotherapy. DNA is not a major pharmacological target of gold-based drugs, rather, the inhibition of other enzymes are involved.
Applications of gold carbene complexes are beginning to emerge in the medicinal and biochemical fields [H. G. Raubenheimer, S. Cronje, Chem. Soc. Rev. 37 (2008) 1998-2011—incorporated herein by reference in its entirety]. The antiarthritic gold(I) phosphine compound, auranofin (AF) shows interesting antitumor in vitro as well as in vivo activity. It also inhibits glutathione S-transferase expression in several chemoresistant tumors [R. Noghuchi, A. Hara, A. Sugie, K. Nomiya, Inorg. Chem. Commun. 9 (2006) 355-359—incorporated herein by reference in its entirety]. Ott pointed out that N-heterocyclic carbenes (NHCs) are an interesting class of ligands that mimic phosphines with donor properties [I. Ott, Coord. Chem. Rev. 253 (2009) 1670-1681—incorporated herein by reference in its entirety]. Baker et al. reported the mononuclear, cationic, linear Au(I) N-heterocyclic carbene species induce dose-dependent mitochondrial swelling in an isolated rat liver [M. V. Baker, P. J. Barnard, S. J. Berners-Price, S. K. Brayshaw, J. L. Hickey, B. W. Skelton, A. H. White, Dalton Trans. 30 (2006) 3708-3715—incorporated herein by reference in its entirety]. Barnad et al. also described a series of bis-NHC-gold(I) complexes that induce mitochondrial swelling, which was directly affected by lipophilicity [P. J. Barnard, S. J. Berners-Price, Coord. Chem. Rev. 251 (2007) 1889-1902—incorporated herein by reference in its entirety]. Siciliano et al. prepared bis(1,3-dimethylimidazol-2-ylidene) gold(I) nitrate and bis(4,5-dichloro-1,3-dimethylimidazol-2-ylidene)gold(I) nitrate salts via transmetallation of their silver precursors with chloro dimethylsulfide gold and determined the anticancer properties using NCI-H460 lung cancer cells [T. J. Siciliano, M. C. Deblock, K. M. Hindi, S. Durmus, M. J. Panzner, C. A. Tessier, W. J. Youngs, J. Organomet. Chem. 696 (2011) 1066-1071—incorporated herein by reference in its entirety].
Gold complexes with dithiocarbamate ligands have also emerged as anticancer agents and have shown much promising results [G. Boscutti, L. Feltrin, D. Lorenzon, S. Sitran, D. Aldinucci, L. Ronconi, D. Fregona, Inorg. Chim. Acta 393 (2012) 304-317—incorporated herein by reference in its entirety]. Ronconi et al. prepared and characterized some novel gold(III) dithiocarbamate compounds containing N,N-dimethyldithiocarbamate and ethyl sarcosine dithiocarbamate, demonstrating very encouraging chemical and biological profiles [L. Ronconi, L. Giovagnini, C. Marzano, F. Bettio, R. Graziani, G. Pilloni, D. Fregona, Inorg. Chem. 44 (2005) 1867-1881—incorporated herein by reference in its entirety]. Further, the treatment with dibromo(N,N-dimethyldithiocarbamato) gold(III) complex resulted in significant inhibition of in vivo MDA-MB-231 breast tumor growth [V. Milacic, D. Chen, L. Ronconi, K. R. Landis-Piwowar, D. Fregona, Q. P. Dou, Cancer Res. 66 (2006) 10478-10486—incorporated herein by reference in its entirety]. Zhang et al. reported gold(I)-dithiocarbamato species, namely [Au(ESDT)] could inhibit the chymotrypsin-like activity of purified 20S proteasome and 26S proteasome in human breast cancer MDA-MB-231 cells [X. Zhang, M. Frezza, V. Milacic, L. Ronconi, Y. Fan, C. Bi, D. Fregona, Q. P. Dou, J. Cell. Biochem. 109 (2010) 162-172—incorporated herein by reference in its entirety].
Worldwide, lung and colorectal cancers are common causes of cancer-related death in men and women while cervical cancer is a major cause of cancer death among women [K. Nomiya, R. Noghuchi, K. Ohsawa, K. Tsuda, M. Oda, J. Inorg. Biochem. 78 (2000) 363-370—incorporated herein by reference in its entirety]. Chemotherapy is still the primary method for treating cancers followed by radiotherapy. Nevertheless, there are some major challenges for treating cancers which include intrinsic resistance of cancer to chemotherapy, different phenotypes of cancer, and systemic toxicity issues. Therefore, new chemotherapeutic modalities are required. New gold carbene complexes are being developed by incorporating activity-enhancing and bio-acceptable co-ligands like dithiocarbamate with specific inherent properties for biomedical applications. Based on this strategy, a novel series of gold(I) complexes may be developed with new combination of C and S donor atoms of carbene and dithiocarbamate ligands respectively that show enhanced selectivity for such resistant cancers and with fewer side-effects in comparison to platinum-based drugs.
In view of the forgoing, the objective of the present disclosure is to provide N-heterocyclic carbene gold(I) dithiocarbamate complexes with efficacy against, and selectivity towards, cancers that are resistant to platinum-based chemotherapeutic agents, while also providing fewer side effects.